Cholangiocarcinomas are malignancies of the biliary tract that are increasing in incidence globally. These tumors respond poorly to conventional therapeutic approaches and are typically associated with a poor prognosis. Our long-term goal is to define the cellular mechanisms responsible for tumor development and progression in biliary epithelia and to develop new therapies for cholangiocarcinoma. Interleukin-6 (IL-6) is an autocrine factor contributing to cholangiocarcinoma growth, and furthermore can promote cell survival. Dysregulation of cell survival mechanisms are critical for tumor growth and progression. Thus, the overall objective of this proposal is to define the cellular mechanisms by which aberrant cellular survival signaling by IL-6 contributes to cholangiocarcinoma formation, progression and resistance to therapy. Our preliminary data suggest that IL-6 inhibits apoptosis, and stimulates p38 Mitogen activated protein kinase (MAPK) signaling pathways that are involved in transformed cell growth in malignant cholangiocytes, as well as in modulation of protein synthesis by altering initiation of translation. Based on this information, we have proposed the central hypothesis that IL-6 promotes cholangiocarcinoma growth by activation of p38 MAPK dependent survival pathways. We will test this central hypothesis in three specific aims. The first specific aim is to test the hypothesis that IL-6 activates the survival kinase SGK by activation of specific p38 MAPK isoforms in an Src-dependent manner. The second specific aim is to test the hypothesis that p38 MAPK signaling regulates translational expression of the X-linked inhibitor of apoptosis protein by IL-6. The third specific aim will test the hypothesis that autocrine IL-6 stimulation contributes to tumor formation, growth and resistance to therapy by inhibiting apoptosis. The mechanisms of IL-6 signaling, intracellular survival kinase activation, and translational regulation of gene expression as well as tumor formation and growth in vivo will be assessed. We have established complementary cell-culture systems, cell-free systems, and animal models of tumor growth for these studies. Successful completion of the proposed studies will facilitate the development of new therapeutic interventions to prevent and treat cholangiocarcinoma.